Synthesis of 2,3-substituted indoles

ABSTRACT

A process for the production of 2,3-substituted indoles from Alpha -haloaldehydes or derivatives thereof and certain primary or secondary aromatic amines is disclosed. These indoles are useful in the production of Fischer type bases which are utilized as intermediates for the synthesis of cyanine dyes and photochromic compositions.

United States atent n91 Krutak, Sr.

[ SYNTHESIS OF 2,3-SUBSTITUTED INDOLES [75] Inventor: James J. Krutak, Sr., Kingsport,

Tenn.

[73} Assignee: Eastman Kodak Company,

Rochester, NY.

[22] Filed: May I, 1974 [2]] Appl. No.: 465,980

Related US. Application Data [63] Continuation of Ser. No. 264,687, June 20. I972.

abandoned [52] US. Cl. 260/319.1 [51] Int. Cl. C07D 209/04; CO7D 209/08 [58] Field of Search 260/319.1

[56] References Cited OTHER PUBLICATIONS Sundberg, The Chemistry of Indoles, (1970) pp.

[4 1 Sept. 16, 1975 Elderfield, Heterocyclic Cmpds.." Vol. 3, pp. 24-25.

Primury Examiner-Lewis Gotts Assistant lira'minerS. P. Williams Attorney, Agent, or Firm-Elliott Stern; Daniel B. Reece, lll

[ 5 7 ABSTRACT 3 Claims, N0 Drawings 1 SYNTHESIS OF 2,3-SUBSTITUTED INDOLES This is a continuation of application Ser. No. 264,687, filed June 20; 1972, now abandoned.

This invention relates to a process for the preparation of 2,3-substituted indoles. More particularly, this invention relates to a novel processfor the production of 2,3-substituted indoles from a-haloaldehydes or derivatives thereof and certain primary or secondary aromatic amines. These indolesare useful for many applications such as the production of Fischer type bases which are utilizedas intermediates for the synthesis of cyanine dyes and photochromic compositions.

By indole it is meant one of a group of organic heterocyclic compounds in which a benzene ring is fused to a pyrrole ring according to the following formula:

Zone of acetone, the product is 2-methyl indole. Offur-' ther interest is US. Pat. No. 3.534,()59 issued Oct. 13,

1970, and US. Pat. No. 2,765,300 issued Oct. 2, 1956. Although these prior known processes can be used to produce indoles, they leave much to be desired from a commercial standpoint.

Therefore, an object of the present invention is to provide a new process which can be practiced on a commercial scale for the production of2,3-substituted indoles by the reaction of ana-haloaldehyde or derivatives thereof with certain aromatic amines.

Other objects will become apparent from the following description of the invention.

According to this invention it has been found that 2,3-substituted indoles can be prepared by a process which comprises admixing one mole proportion of an a-haloaldehyde or derivatives thereof to at least onemol proportion of an aromatic, primary or secondary amine at a temperature vof from about 100 to about 210C. for a period ofyat least about 30 min; the aromatic amine containingo nuclear carbon atoms, from 6 to about 30 carbon atoms in the total molecule, and at least one hydrogen attached to the nitrogen of the amino group and at least one hydrogen on the aromatic nucleus ortho to theamino group.

The term a-haloaldehyde or derivative thereof refers to a group of compounds having thefollowing structure wherein R and R are the same or different and each repre- 6g where m is a positive integer of 4, 5 or 6 and n is a positive integer of 2, 3 or 4; X represents chloro, bromo or Y represents oxygen or each R is the same or different and represents hydro gen, alkyl, halogen, .alkoxy, alkanoylamino, alkoxycarbonyl or alkyl substituted with halogen, hydroxy,

-SO F, cyano'or alkanoylamino,

z represents a'positive integer from 1 to 4; and R represents hydrogen, alkyl, or alkyl substituted with halogen, hydroxy, alkanoylamino or cyano.

Examplesof the groups represented by R are chloro, bromo, methoxy, ethoxy, butoxy, propoxy, NH-

COCH;;. NHCOC H COOCH COOC H chloroethyl, bromomethyl, bromobutyl, h'ydroxyethyl, hy-" droxypropyl,'cyanoethyl, cyanobutyl, acetamidoethyl,

acetamidopropyl, SO CH etc.

Examples of suitable substituted lower alkyl groups represented by R are hydroxyethyl, hydroxybutyl, cyanomethyl, cyanoethyl, cyanobutyl, bromomethyl, chloroethyl, acetamido ethyl, acetamidobutyl, ethoxyethyl, methoxyethyl, etc.

In a preferred embodiment of this invention R, R R and R represent the above mentioned radicals except that the groups that contain alkyl moieties from 1 to about 6 carbon atoms.

As used-herein to describe asubstituent containing an alkyl moiety, the word "lower""designates a carbon content of up to about 6 carbon atoms.

In an especially preferred embodiment of this invention R and R are lower alkyl;

R is hydrogen, lower alkyl or alkoxy;

1 is l or 2;

R" is hydrogen or lower alkyl;

X is chloro or bromo, and

. Y is oxygen. 3

I The aldehydes and the aromatic amines useful in this invention are well-known compounds and are either available commercially or are readily prepared by wellgents employed. The time required to complete the reknown procedures. The compounds represented by the actions will vary with the reactants. however. it has been found that periods of greater than 30 minutes are usually sufficient to complete the reaction. preferably 5 at least about 2 hours.

Y Generally speaking the process may be conducted X-C---(--H under standard atmospheric pressure in an atmosphere of nitrogen. Since the products will autooxidize when dissolved in non-polar solvents containing oxygen. it is desirable to carry out the reaction in the absence of oxygen. Thus. an inert gas blanket is normally used. The reagents may be generally employed in a ratio of l y "3x mole proportion of oz-haloaldehyde or a derivative fir and/Or s respectively thereof to at least 3 mole proportions of aromatic l5 amines. preferably at least 5 mole proportions of arematic amines. An excess of aromatic amine is used in this reaction in order to provide the reaction with a proton acceptor to accept the acid which is produced by the reaction. This reaction proceeds according to general formula may be prepared according to the following reaction sequence (a-chloroisobutyraldehyde and aniline are used as representative examples for the general reaction):

CH... 0 CH OH CH I ii I l o I CICC -NH ClC"CN ci-c -c=N H 0 1 l I I CH. CH H H CH. H

a-Chloroisohutyraldehyde a-Chloroisohutyraldehydc anil A C. -NH

9' ii NC-("-H N C---C=N H I I l CH;. (H H a-anilinoisobutyraldchyde a-anilinoisobutyraldehyde anil Any of a wide variety of aromatic amines may be utithe following equation (a-chloroisobutyraldehyde and lized in the process of this invention. the only requireaniline are used as examples for the general reaction):

ment being that the amine contain at least one hydrogen suhstituent on the aromatic nucleus ortho to the amino group and at least one hydrogen atom on the (H 0 o ammo group itself. lhe aromanc amine may contain any of a wide variety of substituents on the nucleus and --+I 'i 1 6N2-HCI the nitrogen atom of the amino group. The preferred \N/ amine reagent is depicted by the following structural l formula:

Alternatively 1 mole proportion of a-haloaldehyde H and 1 mole proportion of aromatic amine may be used R 0: in the presence of a proton accepting reagent such as 2X s El? triethylamine. pyridine. dimethyl pyridine. alkali metal carbonates. bicarbonates or acetates. A1 BaO. Cawherein R. R and Z are defined as above. ((,)H). CaO. etc. Generally. this reaction proceeds at The process is to be conducted at temperatures temperatures from about l00 to about 150C. This rewhich are sufficient to produce the desired indole prodaction proceeds according to the following general uct but insufficient to decompose the product. These equation (01-hromoisobutyraldehyde and N-methyl-4- results are achieved by conducting the process at a ethylaniline are used as examples for the general reactemperature within the range of from about to tion):

0 I 0 A 4 0:0 Ii-l %N/ zHg-f R- -fi-CH; f o 0 Cal-i5 W Br t; v H A 9 K cH: g

CHa CH3 N '3 IHa about 2l0C.. preferably to about 200C. Of After the reaction has proceeded for at least about 30 course. the preferred or optimum temperature varies minutes. and preferably about 2 hours the reaction between these ranges depending upon the specific reamixture may be cooled and poured onto sufficient hydrogen chloride, ice and water to neutralize an excess aromatic amines or proton accpeting reagent such as pyridine. The 2,3-substituted indole products are insoluble and separate as a powder or oil and may be iso lated by filtration or extraction with a suitable organic solvent such as methylene chloride,etc. ln-order to ob-- recycled by neutralization of the aqueous phase with sodi-unrhydrox-ide or anyothersuitable base, mechanical separation of the amine and distillation.

The indoles generated bythe. solvent process of this inventionv using para-substitutedprimary or secondary amines may be directly converted to Fischers'base compounds substituted in the 5-positionby conducting the reaction in the presence of a polyphosphate ester (see application Ser. No. 264,690 filed June 20, 1972, now abandoned)" The novel" compounds formed thereby can then be directly reacted with any ofa large number of compounds which have previously been used to form cyanine dyesor cyanine dye intermediates. The novel process ofthis invention therefore may be utilized as they first step for an=eco nomica1one .part process for the production of cyaninedye or cyanine dye intermediates. o o I The following cxamplesare included for a better understanding of this invention.

EXAMPLE 1 N-ethyl aniline (5 moles) is degassed with nitrogen in a 1000 ml. flask, and stirred under an atmosphere of nitrogen. a-Chloroisobutyraldehyde (1 mole) is added at 100C. and the exothermic reaction is easily controlled or maintained at reflux temperature of about 130 to 140C. for minutes. The reaction temperature is raised to 180C. by distilling out water of con densation. After 4 hours at 180C. the mixture is cooled and poured into sufficient hydrogen chloride and ice and water to neutralize the excess N- ethylaniline. The product formed has the following structural formula and is obtained in a 60% yield.

EXAMPLE 2 Preparation of a-Anilinoisobutyraldehyde.

A solution of 0.50 mole aniline and 0.50 mole triethylamine in 50 g. pxylene is prepared, stirred vigorously under a nitrogen atmosphere in a 1000 ml. flask, and treated with 0.50 mole oz-chloroisobutyraldehyde. The

clear solution is heated atthe reflux temperature for 3 hr,., c oo1ed and stirred l8 hr. at roonrternperature. Filtration gives 0.50 moles triethylainine hydrochloride. Petroleum ether (2 00 ml. isadded to the filtrate which is chilled and induced to crystallize. Filtration gives 15 g, of-a-anilinoisobutyraldehyde, m.p. 8791C. (re-.

crystallized from chloroform: petroleum ether).

EXAMPLE 3 Preparation of oz-Chloroisobutyraldehyde Anil.

Aniline (0.2 5 mole) is cooled to 0C. ina 1000 ml. flask and treated with 0.25 mole a-chlo roisobutyraldev hyde; water. rapidly, separates and the equilibrium mix.-

ture is found to contain mole 7( of the a-chlo'robuty- .raldehyde anil, water, and reactants.

The product is isolated in pure form by repeating the above reaction using, however, .a CC1 solventand addinganhydrous MgSO to shift thelequilibrium to completion. Filtration gives a carbon tetrachloride solution of the pure ani1..-

EXAMPLE 4 Preparation of u-Anilinoisobutyraldehyde Anil. A solution of 1 mole a-anilinoisobutyraldehyde and 1 mole anilinein, 200 g. benzene is refluxed in a 1000 ml. flask under a Dean-Stark trap until 1 mole of water is collected. Evaporation of the benzene gives an oil which is shown to be a-anilinoisobutyraldehyde anil.

EXAMPLES 5 The products of Examples 2, 3 and 4 are reacted with aniline under the conditions described in Example 1. In each case the product is high assay 2,3-dimethy1indole.

EXAMPLE 8 A solution of 1 mole of p-toluidine in pyridine (5 moles) is degassed with nitrogen in a 1000 ml. flask and treated with 1 mole of a-chloroisobutyraldehyde. After the exothermic reaction subsides. the solution is heated at reflux temperatures (1 15C.) under an atmosphere of nitrogen for l to 3 hours. cooled, and poured on ice and water containing sufficient hydrogen chloride to neutralize the excess pyridine. The product separates as a fine powder which is filtered, dried. and further purifled by recrystallization. The product is obtained in yield and has the following structural formula:

Similar results are obtained when 2,6-dimethylpyridine is used as a solvent.

EXAMPLES 91 5 The following indoles are prepared in accordance with the procedure described in Example 1 except that the reactants are varied as indicated.

Estimated lsdlillitl Actual Example Amine Aldehyde lndole Product Yield i)? l Yleldfl/l' '9 aniline a-chloroisiihutyraldchyde 2.3-dimethylindole 00 )0 I0 o-anisidinc do. 2,3-diineihyl-7-hiethoxyindulc 5? =90 1 l o-toluidinc do. 2;3=tiifiieihyl=7=lfleihylindole 7Q 10 I2 aniline rx-ehlorodiphenylacetaldehyde 234.11 hellylilititllt: =00 l3 N-metl'lylaniline aehloroisohutyraldehydc l-*fiieiiijyl=. ,3=tllthtth lindolu 33 -40 l4 aniline ix-chlorocyclohexanecarboxaldehydc 2tlpelitill'liifiliyieiicindolc 51 N0 15 aniline Z-ehloro-2-ethylbutyraldchyde aliethylimlnle 65 EXAMPLES lo2] i l I i The following lndoles are prepared in accordance 2X with the procedure described in Example 8. except that l g the reactants are varied as indicated.

Estimated Isolated Actual Yield Yield Exv Amine r Aldehyde Indolc Product (/r) (/1) l6 p-anisidine a-bromoisohutyraldehytle 2.3-dimcthyl-S-methoxyindole, 90 90 l7 p-acctamido anilinc do. 2.3-dimethyl--acctamidoindole 50 90 18 p-chloroaniline I do. 2.3dimcthyl-5-chloroindole 40 90 19" 2 4-dimethoi(yanilinc u-chloroisobutyraldehydc 2.3-dimethyk5.7-dimcthoxyindole 90 20- p toluidine, a-chlorodiphenylacetaldchyde 2,34]iphcnyl-S-methylindole v 90 90 2| p-toluidine a-chlorocyclohexanccarhoxaldchyde 2 3pcntamcthylcne-imethylindolc I 80 90 Althoughthdinventibn has been described in considand heating the admixture for at least about minerable detail with particular reference to certain preutes-at a temperature between 100 and about ferred embodiments thereof. variations and modifica 210C; tions can be effected within the spirit and scope of-the 20 r invention where! R. and R are lower alkyl; Chum R h d lk l l lk 1s ro e1, wwer l o ow r a '0X 1. A method of preparing 2,3-substituted indoles y g l y r y ;islor2; which comprises the steps of. R I d 1 1k 1 admixing 1 mole proportion of a compound having I? s y the formula is c oro or romo. an

. Yrepresents oxygen.

Rl Y

2. Method ofclalm I conducted in the presence of at I'- 1- w least 3'molc proportions of amine. g H I R'-' 1 V v 3. Method of claim l conducted in at least 1 mole to at least 1 mole proportion of an amine having the proportion of a proton accepting reagent.

formula (ill 

1. A METHOD OF PREPARING 2,3-SUBSTITUTED INDOLES WHICH COMPRISES THE STEPS OF: ADMIXING 1 MOLE PROPORTION OF A COMPOUND HAVING THE FORMULA
 2. Method of claim 1 conducted in the presence of at least 3 mole proportions of amine.
 3. Method of claim 1 conducted in at least 1 mole proportion of a proton accepting reagent. 